Infection outbreaks are usually recognised when an unexpectedly high number of cases of a clinical illness are observed. With hepatitis B infection, the incubation period is long and a substantial proportion of infected people—especially children and the immunocompromised host—may remain asymptomatic.1-3 These factors increase the risk of prolonged and unrecognised outbreaks. Denmark has not implemented universal childhood hepatitis B immunisation, and vaccination is not required for health workers performing invasive procedures.
Phylogenetic analysis of hepatitis B virus have been used to investigate recognised outbreaks,4,5 to reject or confirm suspected chains of transmission,6 and to prove unusual reservoirs or routes of infection.7,8 We present the unravelling of an outbreak of asymptomatic hepatitis B on a paediatric ward after the incidental identification of a single case of hepatitis B. The recognition and subsequent halting of the spread of this outbreak were possible owing to the availability of a DNA sequences library compiled from patients with hepatitis B in the locality.9
Case description
During preparation for bone marrow transplantation, a child was diagnosed with an acute asymptomatic hepatitis B infection at the paediatric haematology and oncology department at Odense University Hospital. Screening for hepatitis B had been negative two years previously, and serology testing and polymerase chain reaction in repository blood donation samples and follow-up samples from all involved blood donors were negative for the virus. The patient had had no contact with known hepatitis B cases during the suspected incubation period.
As part of a research programme, strains of the hepatitis B virus consecutively detected in the area had been partially sequenced. The patient's sequence (the hepatitis B epi strain) was identical to that of a known hepatitis B carrier who had been admitted to the ward 14 months earlier but to whom our case had no connection in time or place. It was suggested that more cases might therefore be involved in the transmission, and an outbreak investigation was launched.
Figure 1.
Molecular epidemiology may identify hospital based outbreaks quickly by revealing unsuspected transmission routes
Credit: GUSTO/SPL
Ward description
The 10 bed ward served as the paediatric haematology and oncology centre of southern Denmark. Patients needing multiple infusions or intravenous chemotherapy had a central venous catheter inserted, and the catheters were used for blood sampling whenever possible. Handling of central venous catheters was described in written instructions that complied with universal precautionary measures. All intravenous injections and infusions were administered on the ward.
Cancer chemotherapy and blood components were delivered ready for infusion to the ward's drug preparation room, where all other intravenous medications were prepared. Saline and heparin aspirated from multidose phials in the preparation room were used when central venous catheters were flushed and sealed. Aspiration needles were not left in these phials.
Patients admitted with a malignant illness were screened for hepatitis B infection at first admission but with no routine follow-up.
Outbreak investigation
EDTA plasma was analysed for hepatitis B surface antigen and for antibodies to hepatitis B core antigen (AxSYM series assays, Abbott Diagnostic Division, Germany). DNA was isolated, and part of the hepatitis B virus S gene was amplified, sequenced, and subjected to phylogenetic analysis as described previously.9
The hospital's infection control team investigated ward facilities and procedures involving contact with blood, body fluids, and secretions. The investigations covered blood sampling; handling and maintenance of intravenous catheters; intravenous medications and transfusions; and disposal of material contaminated with blood, body fluids, or secretions.
Hepatitis B testing was offered to patients admitted in the period from the source patient's initial admission until procedures were corrected. In addition, members of the infected patients' households and staff were surveyed, and susceptible individuals were vaccinated.
We reviewed hospital records of infected patients. Data on age, sex, diagnosis, treatment (including insertion of central venous catheters), and dates of admissions and discharges were retrieved from the hospital database in all patients.
Results
We identified 175 patients, of whom we excluded the source and index patients, a patient who had already been infected with hepatitis B, 15 patients who died of their malignancy, and two patients lost to follow-up. Of the remaining 155 patients, 133 (86%) accepted screening. Unscreened patients had a single hospital stay of short duration and, except for one patient, had not had a central venous catheter inserted.
Apart from the index and source patients, seven patients and two relatives were HBsAg positive. One patient (receiving immunoglobulin substitution) and a sibling (without risk factors for hepatitis B) of another patient had antibodies to hepatitis B core antigen and to hepatitis B surface antigen. No staff member was infected. The hepatitis B epi strain was isolated from six of the patients; the other patient and the two relatives had unrelated strains and had (previously unknown) chronic hepatitis B infection—probably related to the fact that these three individuals had been born and raised in areas with a high prevalence of hepatitis B. Hence the outbreak consisted of the source patient and seven definite and two possible cases. All case patients remained positive for hepatitis B e antigen during follow-up, and none have had clinical disease.
Hepatitis B infection correlated significantly with the insertion of a central venous catheter (table). Disease category, time of initial admission, age, and sex were unrelated to hepatitis B transmission.
Table 1.
Hepatitis B infection associated with central venous catheters among 131 children on an haematology and oncology ward. Values are numbers (percentages) of children, unless stated otherwise
| Positive for hepatitis B | Negative for hepatitis B | P value* | |
|---|---|---|---|
| Central venous catheter | |||
| Ever patients
|
7 (100)
|
41 (33)
|
0.0007 |
| Never patients | 0 | 83 (67) |
Fisher's exact test.
The only identifiable breaches in hygiene were associated with the ward's preparation room, which was used for collecting blood samples, drying bone marrow smears, and (in periods of overcrowding) occasionally for blood sampling and transfusions, and multidose phials in use were placed next to the disposal pot for used infusion bags and lines, syringes, needles, and blood samples. As both sterile and non-sterile procedures were performed in the preparation room, the infection control team concluded that unintentional contamination of multidose phials and/or other intravenous preparations might have occurred.
Identified hazardous procedures were corrected immediately. The preparation room is now used for sterile procedures only; blood, body fluids, and used equipment are disposed of elsewhere; and single use phials have replaced multidose phials. Since these changes, no new cases of hepatitis B have been identified during active surveillance.
Discussion
To our knowledge, this is the first hepatitis B outbreak to be identified after the recognition of only one asymptomatic case. We began to investigate only because an otherwise unrecognised relation between the index case and a known carrier was established at the molecular level. If this molecular approach had not been available, this outbreak, already affecting 15% of surveyed ward patients with central venous catheters, would have probably propagated unnoticed for a long time. Any new bloodborne viral infection in a high risk setting should therefore raise the suspicion of hospital based transmission. Individual patients' dates of admissions and hepatitis B serology show that viral transmission probably occurred during at least three different time periods.
Although hepatitis B had not been isolated from the ward environment, the implicated route of transmission—on the basis of investigations by epidemiological and infection control teams—was probably central venous catheters and unintentionally contaminated multidose phials and/or other intravenous preparations. Similar transmission modes have been implicated in previous reports on both hepatitis B and less contagious bloodborne pathogens such as hepatitis C, HIV, and Plasmodium falciparum.4,10-14 Overcrowding and the use of the sterile preparation room as a multifunctional facility are believed to have increased the risk of such unintentional incidents. The implication of such breaches in hygiene is supported by the observed interruption of transmission after the hygiene procedures were improved. This outbreak of asymptomatic hepatitis B was identified by molecular epidemiology, and surveillance at the molecular level may be a valuable tool in reducing hospital based transmission.
We thank Kirsten Riisom for supplying information on the index patient's hepatitis serology and transfusion history at the bone marrow transplant centre and Jakob v B Hjelmborg for statistical discussions and advice.
Contributors: All authors helped to collect and analyse the data and prepare the manuscript. LT-S and NF identified the index case as “suspicious,” planned and conducted the initial blood donor investigation, and supplied serology results. NF supplied and analysed molecular data. NLTC and AH supplied clinical data retrieved from the hospital database. NLTC reviewed patient files and organised the seroepidemiological investigations, which were planned by NF, NLTC, HJK, AH, PBC; HJK conducted hygiene investigations. NF computerised the data. Analysis and interpretation was conducted by NF and agreed on by all authors. NF wrote the initial draft; and NF and PBC revised it. All authors approved the final manuscript. NF is the guarantor.
Competing interests: None declared.
References
- 1.McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151: 599-603. [DOI] [PubMed] [Google Scholar]
- 2.Hadler SC, Judson FN, O'Malley PM, Altman NL, Penley K, Buchbinder S, et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J Infect Dis 1991;163: 454-9. [DOI] [PubMed] [Google Scholar]
- 3.Bruguera M, Vidal L, Sanchez TJ, Costa J, Revert L, Rodes J. Incidence and features of liver disease in patients on chronic hemodialysis. J Clin Gastroenterol 1990;12: 298-302. [DOI] [PubMed] [Google Scholar]
- 4.Dumpis U, Kovalova Z, Jansons J, Cupane L, Sominskaya I, Michailova M, et al. An outbreak of HBV and HCV infection in a paediatric oncology ward: epidemiological investigations and prevention of further spread. J Med Virol 2003;69: 331-8. [DOI] [PubMed] [Google Scholar]
- 5.Christensen PB, Krarup HB, Niesters HG, Norder H, Schaffalitzky de Muckadell OB, Jeune B, et al. Outbreak of hepatitis B among injecting drug users in Denmark. J Clin Virol 2001;22: 133-41. [DOI] [PubMed] [Google Scholar]
- 6.Norder H, Hammas B, Lindgren A, Lindholm A, Ekermo B, Garpenholt Ö, et al. Confirmation of transmission links for hepatitis B virus by limited sequencing: Presumed post transfusion hepatitis B may often be nosocomially transmitted. In: Ghnassia JC, Harzic M, Maisonneuve P, Noël L, eds. IXe Colloque de Virologie de Versailles-Le Chesnay. New York: Springer, 1995: 39-50.
- 7.Tedder RS, Zuckerman MA, Goldstone AH, Hawkins AE, Fielding A, Briggs EM, et al. Hepatitis B transmission from contaminated cryopreservation tank. Lancet 1995;346: 137-40. [DOI] [PubMed] [Google Scholar]
- 8.Osterhaus AD, Vos MC, Balk AH, de Man RA, Mouton JW, Rothbarth PH, et al. Transmission of hepatitis B virus among heart transplant recipients during endomyocardial biopsy procedures. J Heart Lung Transplant 1998;17: 158-66. [PubMed] [Google Scholar]
- 9.Fisker N, Pedersen C, Lange M, Nguyen NTT, Nguyen KTT, Georgsen J, et al. Molecular epidemiology of hepatitis B virus infections in Denmark. J Clin Virol 2004;31: 46-52. [DOI] [PubMed] [Google Scholar]
- 10.Kidd-Ljunggren K, Broman E, Ekvall H, Gustavsson O. Nosocomial transmission of hepatitis B virus infection through multiple-dose vials. J Hosp Infect 1999;43: 57-62. [DOI] [PubMed] [Google Scholar]
- 11.Widell A, Christensson B, Wiebe T, Schalen C, Hansson HB, Allander T, et al. Epidemiologic and molecular investigation of outbreaks of hepatitis C virus infection on a pediatric oncology service. Ann Intern Med 1999;130: 130-4. [DOI] [PubMed] [Google Scholar]
- 12.Krause G, Trepka MJ, Whisenhunt RS, Katz D, Nainan O, Wiersma ST, et al. Nosocomial transmission of hepatitis C virus associated with the use of multidose saline vials. Infect Control Hosp Epidemiol 2003;24: 122-7. [DOI] [PubMed] [Google Scholar]
- 13.Katzenstein TL, Jorgensen LB, Permin H, Hansen J, Nielsen C, Machuca R, et al. Nosocomial HIV-transmission in an outpatient clinic detected by epidemiological and phylogenetic analyses. AIDS 1999;13: 1737-44. [DOI] [PubMed] [Google Scholar]
- 14.Abulrahi HA, Bohlega EA, Fontaine RE, al Seghayer SM, al Ruwais AA. Plasmodium falciparum malaria transmitted in hospital through heparin locks. Lancet 1997;349: 23-5. [DOI] [PubMed] [Google Scholar]